Cervical Cancer is the second most common type of cancer in women worldwide and the leading cause of cancer related mortality in women in developing countries. Early detection and diagnosis can saves lives and reduce the burden on the national healthcare system. We have built a non-invasive research-prototype point-of-care device to detect early cancerous conditions of the uterine cervix. We have tested this prototype in a multi-center national study accruing data from 600 women for training our algorithm. Through conversations with the FDA we now have in place a pivotal trial protocol for validating our algorithm. We will use a pre-production version of our device in this pivotal study. The pre-production device is will be a cost and size reduced, portable, rugged and user-friendlier device and is intended to be identical to the device intended for sale without incurring the tooling costs necessary to enter the production phase.
Epithelial cancers collectively constitute about 90% of all cancer occurrences. Common epithelial cancers include skin, cervical, GI tract, colon and oral cancer. While the technology we have developed is generic and applicable to any accessible epithelial cancer, we have chosen cervical cancer as our first diagnostic target. This is because the cervix is easily accessible and the pathophysiology of cancer progression in it is well understood. Cervical cancer is a leading cause of cancer-related mortality in women in developing countries and the second most common type of cancer in women worldwide. The American Cancer Society estimates that there will be 12,200 new cases of invasive cervical cancer diagnosed in 2003 and about 4,100 women will die from the disease in the US this year. Worldwide, there are approximately 500,000 cases of cervical cancer diagnosed annually and approximately 230,000 deaths per year. Estimates show the market potential for non-invasive cervical cancer detection to be at $1.25 billion annually in the US and Europe.
Cervical cancer screening: The Pap test is currently the most widely used tool to screen women for cervical cancer or neoplasia. While its contribution to reducing patient mortality is widely acknowledged, it is prone to errors from low screening frequency, insufficient cell sampling, inadequate sample preparation, lack of exfoliation of abnormal cells, and technician reading error. The discrimination performance of this test is therefore limited, resulting in a tradeoff between sensitivity and specificity as illustrated in a landmark meta-analysis conducted by Fahey. Current practice sets the sensitivity at 51% in order to achieve a specificity of 97%. Thus, Pap tests have been used as a means to ‘rule out’ rather than ‘rule in’ disease. One rationale behind this is to limit the large number of false positives that would inadvertently burden downstream health management systems. While this may be true, this also results in a deference of diagnosis at an annual cost of nearly $2 billion. Improvements to the traditional Pap test such as ThinPrep® are becoming increasingly popular with physicians. This test contributes to lower intermediate classifications such as ASCUS and increases the percentage of LSIL+ patients sent to colposcopy. Using a different approach, the Digene HPV test used for ASCUS triage appears to be better than a repeat Pap test in finding patients with CIN3 who are referred to colposcopy. In a recent study of 8,170 screened women HPV detected 93.3% of CIN3. However, the sensitivity for CIN2 disease was only 72% so that the overall sensitivity of HPV for HSIL (CIN 2/3 and higher) was 81.8%. Moreover, a low-test specificity results in an increase in false positives. Also, while the FDA has approved computerized aids to Pap test screening such as AutoPap and Papnet, the evidence regarding the impact of these technologies on the screening process is not yet available.
Cervical cancer diagnosis: A positive first or second Pap test is followed by a colposcopic examination. This involves visualization of the cervix under low power magnification by a trained clinician who looks for visual cues attributable to neoplasia. The clinician then takes a tissue biopsy from that location. The amount of tissue biopsied varies according to the extent of the assessed lesion and, in some cases, the entire cervix is removed in what is known as a Loop Electrosurgical Excision Procedure (LEEP). A pathologist whose diagnosis is considered the gold standard examines the biopsy specimens. Since suspect areas are identified visually, colposcopy requires extensive training, experience, and a significant effort toward maintenance of skills.
A key disadvantage of the current methods is the significant time delay in obtaining the results. A patient and care provider must wait 1-4 weeks for the results of the Pap test. Quite often the colposcopy, biopsy and histology sequence has to be repeated in order to localize and diagnose the disease definitively. A point of care approach in new technology will be a significant advantage.
The problem is further compounded by the performance limits of colposcopy. A meta-analysis of colposcopy summarizing the results of 9 studies lists the average sensitivity and specificity at 85% and 69% respectively for separating LSIL and lower (CIN 1 and lower) from HSIL (CIN 2/3 and higher). More recent studies show a much lower sensitivities of 53% and 56%.
Therefore, a strong need clearly exists for better differentiation at any point along the entire screening to diagnosis path. The low specificity and sensitivity numbers result in a large number of patients undergoing unnecessary biopsy and/or a large number of patients with cancer going untreated. Moreover, the one to four weeks required to obtain a Pap test result or a histology evaluation results in increased patient anxiety and/or reduced patient commitment to seeking aggressive treatment. This is especially problematic in treating patients in developing countries and with indigent populations in the US and other developed countries. Given that these are the same populations with the highest prevalence of cervical disease, a point-of-care approach would have greater value in overall disease management. Similar approaches have successfully emerged in other areas of diagnosis and testing such as ‘stat’ blood gas and blood chemistry analysis as well as in home immuno-chemistry assays. In addition there is a need for a less traumatic diagnostic method.